Method for producing difluoromethylene compound

Abstract

The present invention provides a method for producing a difluoromethylene compound and an intermediate thereof, which are useful in the field of pharmaceuticals.Specifically provided is a method for producing a difluoromethylene compound, including a step of allowing a compound represented by formula (6):[wherein L1 represents a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo-lower alkoxy group, or a hydroxy lower alkyl group; R1 represents a lower alkyl group, a halogen atom, a halo-lower alkyl group, a cycloalkyl group, a cyano group, or a hydroxy lower alkyl group; and W represents a nitrogen atom or a methine group] to react with a compound represented by formula (7):[wherein R2 represents a lower alkyl group, a halo-lower alkyl group, a cycloalkyl group, a lower alkenyl group, or an aralkyl group; and R3 represents a chlorine atom, a bromine atom, or an iodine atom].

The invention claimed is: 
     
       1. A method for producing a compound represented by formula (9): 
       
         
           
           
               
               
           
         
         [wherein
 L 1  represents a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo-lower alkoxy group, or a hydroxy lower alkyl group; 
 R 1  represents a lower alkyl group, a halogen atom, a halo-lower alkyl group, a cycloalkyl group, a cyano group, or a hydroxy lower alkyl group; and 
 W represents a nitrogen atom or a methine group], 
 the method comprising the following steps (A) to (F): 
 a step (A): a step of allowing a compound represented by formula (1): 
 
       
       
         
           
           
               
               
           
         
         [wherein R 1 , and W are as defined above] 
         to react with a compound represented by formula (2): 
       
       
         
           
           
               
               
           
         
         [wherein
 L 1  is as defined above; 
 L 2  is a halogen atom or a group represented by —OSO 2 R 4 ; 
 R 4  represents a lower alkyl group, a halo-lower alkyl group, or an aryl group (wherein the aryl group is optionally substituted with a halogen atom, a lower alkyl group, or a lower alkoxy group); 
 LG is a halogen atom or a group represented by —OSO 2 R 5 ; and 
 R 5  represents a lower alkyl group, a halo-lower alkyl group, or an aryl group (wherein the aryl group is optionally substituted with a halogen atom, a lower alkyl group, or a lower alkoxy group)] 
 
         to give a compound represented by formula (3): 
       
       
         
           
           
               
               
           
         
         [wherein L 1 , L 2 , R 1 , and W are as defined above],
 a step (B): a step of cyanating L 2  of the compound represented by formula (3) to give a compound represented by formula (4): 
 
       
       
         
           
           
               
               
           
         
         [wherein L 1 , R 1 , and W are as defined above],
 a step (C): a step of reducing a nitro group of the compound represented by formula (4) to give a compound represented by formula (5): 
 
       
       
         
           
           
               
               
           
         
         [wherein L 1 , R 1 , and W are as defined above] 
         or a salt thereof,
 a step (D): a step of halogenating an amino group of the compound represented by formula (5) or salt thereof to give a compound represented by formula (6): 
 
       
       
         
           
           
               
               
           
         
         [wherein L 1 , R 1 , and W are as defined above, and X L  is a halogen atom],
 a step (E): a step of allowing the compound represented by formula (6) to react with a compound represented by formula (7): 
 
       
       
         
           
           
               
               
           
         
         [wherein
 R 2  represents a lower alkyl group, a halo-lower alkyl group, a cycloalkyl group, a lower alkenyl group, or an aralkyl group; and 
 R 3  represents a chlorine atom, a bromine atom, or an iodine atom] to give a compound represented by formula (8): 
 
       
       
         
           
           
               
               
           
         
         [wherein L 1 , R 1 , R 2 , and W are as defined above], and
 a step (F): a step of removing R 2  of the compound represented by formula (8). 
 
       
     
     
       2. A method for producing a compound represented by formula (9): 
       
         
           
           
               
               
           
         
         [wherein
 L 1  represents a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo-lower alkoxy group, or a hydroxy lower alkyl group; 
 R 1  represents a lower alkyl group, a halogen atom, a halo-lower alkyl group, a cycloalkyl group, a cyano group, or a hydroxy lower alkyl group; and 
 W represents a nitrogen atom or a methine group], 
 the method comprising the following steps (B) to (F): 
 a step (B): a step of cyanating L 2  of a compound represented by formula (3): 
 
       
       
         
           
           
               
               
           
         
         [wherein
 L 1 , R 1 , and W are as defined above; 
 L 2  is a halogen atom or a group represented by —OSO 2 R 4 ; and 
 R 4  represents a lower alkyl group, a halo-lower alkyl group, or an aryl group (wherein the aryl group is optionally substituted with a halogen atom, a lower alkyl group, or a lower alkoxy group)] 
 
         to give a compound represented by formula (4): 
       
       
         
           
           
               
               
           
         
         [wherein L 1 , R 1 , and W are as defined above], 
         a step (C): a step of reducing a nitro group of the compound represented by formula (4) to give a compound represented by formula (5): 
       
       
         
           
           
               
               
           
         
         [wherein L 1 , R 1 , and W are as defined above] 
         or a salt thereof,
 a step (D): a step of halogenating an amino group of the compound represented by formula (5) or salt thereof to give a compound represented by formula (6): 
 
       
       
         
           
           
               
               
           
         
         [wherein L 1 , R 1 , and W are as defined above, and X L  is a halogen atom],
 a step (E): a step of allowing the compound represented by formula (6) to react with a compound represented by formula (7): 
 
       
       
         
           
           
               
               
           
         
         [wherein
 R 2  represents a lower alkyl group, a halo-lower alkyl group, a cycloalkyl group, a lower alkenyl group, or an aralkyl group; and 
 R 3  represents a chlorine atom, a bromine atom, or an iodine atom] 
 
         to give a compound represented by formula (8): 
       
       
         
           
           
               
               
           
         
         [wherein L 1 , R 1 , R 2 , and W are as defined above], and
 a step (F): a step of removing R 2  of the compound represented by formula (8). 
 
       
     
     
       3. A method for producing a compound represented by formula (9): 
       
         
           
           
               
               
           
         
         [wherein
 L 1  represents a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo-lower alkoxy group, or a hydroxy lower alkyl group; 
 R 1  represents a lower alkyl group, a halogen atom, a halo-lower alkyl group, a cycloalkyl group, a cyano group, or a hydroxy lower alkyl group; and 
 W represents a nitrogen atom or a methine group], 
 the method comprising the following steps (C) to (F): 
 a step (C): a step of reducing a nitro group of a compound represented by formula (4): 
 
       
       
         
           
           
               
               
           
         
         [wherein L 1 , R 1 , and W are as defined above] 
         to give a compound represented by formula (5): 
       
       
         
           
           
               
               
           
         
         [wherein L 1 , R 1 , and W are as defined above] 
         or a salt thereof,
 a step (D): a step of halogenating an amino group of the compound represented by formula (5) or salt thereof to give a compound represented by formula (6): 
 
       
       
         
           
           
               
               
           
         
         [wherein L 1 , R 1 , and W are as defined above, and X L  is a halogen atom],
 a step (E): a step of allowing the compound represented by formula (6) to react with a compound represented by formula (7): 
 
       
       
         
           
           
               
               
           
         
         [wherein
 R 2  represents a lower alkyl group, a halo-lower alkyl group, a cycloalkyl group, a lower alkenyl group, or an aralkyl group; and 
 R 3  represents a chlorine atom, a bromine atom, or an iodine atom] to give a compound represented by formula (8): 
 
       
       
         
           
           
               
               
           
         
         [wherein L 1 , R 1 , R 2 , and W are as defined above], and
 a step (F): a step of removing R 2  of the compound represented by formula (8). 
 
       
     
     
       4. A method for producing a compound represented by formula (9): 
       
         
           
           
               
               
           
         
         [wherein
 L 1  represents a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo-lower alkoxy group, or a hydroxy lower alkyl group; 
 R 1  represents a lower alkyl group, a halogen atom, a halo-lower alkyl group, a cycloalkyl group, a cyano group, or a hydroxy lower alkyl group; and 
 W represents a nitrogen atom or a methine group], 
 the method comprising the following steps (D) to (F): 
 a step (D): a step of halogenating an amino group of a compound represented by formula (5): 
 
       
       
         
           
           
               
               
           
         
         [wherein L 1 , R 1 , and W are as defined above] 
         or a salt thereof to give a compound represented by formula (6): 
       
       
         
           
           
               
               
           
         
         [wherein L 1 , R 1 , and W are as defined above, and X L  is a halogen atom],
 a step (E): a step of allowing the compound represented by formula (6) to react with a compound represented by formula (7): 
 
       
       
         
           
           
               
               
           
         
         [wherein
 R 2  represents a lower alkyl group, a halo-lower alkyl group, a cycloalkyl group, a lower alkenyl group, or an aralkyl group; and 
 R 3  represents a chlorine atom, a bromine atom, or an iodine atom] to give a compound represented by formula (8): 
 
       
       
         
           
           
               
               
           
         
         [wherein L 1 , R 1 , R 2 , and W are as defined above], and
 a step (F): a step of removing R 2  of the compound represented by formula (8). 
 
       
     
     
       5. A method for producing a compound represented by formula (9): 
       
         
           
           
               
               
           
         
         [wherein
 L 1  represents a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo-lower alkoxy group, or a hydroxy lower alkyl group; 
 R 1  represents a lower alkyl group, a halogen atom, a halo-lower alkyl group, a cycloalkyl group, a cyano group, or a hydroxy lower alkyl group; and 
 W represents a nitrogen atom or a methine group], 
 the method comprising the following steps (E) to (F): 
 a step (E): a step of allowing a compound represented by formula (6): 
 
       
       
         
           
           
               
               
           
         
         [wherein
 L 1 , R 1 , and W are as defined above; and 
 X L  represents a halogen atom] 
 
         to react with a compound represented by formula (7): 
       
       
         
           
           
               
               
           
         
         [wherein
 R 2  represents a lower alkyl group, a halo-lower alkyl group, a cycloalkyl group, a lower alkenyl group, or an aralkyl group; and 
 R 3  represents a chlorine atom, a bromine atom, or an iodine atom] 
 
         to give a compound represented by formula (8): 
       
       
         
           
           
               
               
           
         
         [wherein L 1 , R 1 , R 2 , and W are as defined above], and
 a step (F): a step of removing R 2  of the compound represented by formula (8). 
 
       
     
     
       6. A method for producing a compound represented by formula (8): 
       
         
           
           
               
               
           
         
         [wherein
 L 1  represents a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halo-lower alkoxy group, or a hydroxy lower alkyl group; 
 R 1  represents a lower alkyl group, a halogen atom, a halo-lower alkyl group, a cycloalkyl group, a cyano group, or a hydroxy lower alkyl group; 
 R 2  represents a lower alkyl group, a halo-lower alkyl group, a cycloalkyl group, a lower alkenyl group, or an aralkyl group; and 
 W represents a nitrogen atom or a methine group], 
 the method comprising the following step (E): a step of allowing a compound represented by formula (6): 
 
       
       
         
           
           
               
               
           
         
         [wherein
 L 1 , R 1 , and W are as defined above; and 
 X L  is a halogen atom] 
 
         to react with a compound represented by formula (7): 
       
       
         
           
           
               
               
           
         
         [wherein
 R 2  is as defined above; and 
 R 3  represents a chlorine atom, a bromine atom, or an iodine atom]. 
 
       
     
     
       7. The method according to any one of  claims 1  to  5  and  6 , wherein R 1  is a lower alkyl group, and/or; wherein L 1  is a lower alkyl group; and/or wherein W is a nitrogen atom. 
     
     
       8. The method according to  claim 1 , wherein a base used in the step (A) is potassium carbonate or cesium carbonate. 
     
     
       9. The method according to  claim 1 , further comprising a step (A-2): a step of recrystallizing the compound represented by formula (3) using a recrystallization solvent that is a combination of tetrahydrofuran and methanol. 
     
     
       10. The method according to  claim 1  or  2 , wherein a cyanating agent used in the step (B) is zinc cyanide, and/or wherein in the step (B), a palladium catalyst or a combination of a palladium catalyst and a phosphine ligand is used. 
     
     
       11. The method according to  claim 1  or  2 , wherein a cyanating agent used in the step (B) is copper cyanide. 
     
     
       12. The method according to any one of  claims 1  to  5  and  6 , wherein R 2  of the compound represented by formula (7) is a lower alkyl group. 
     
     
       13. The method according to  claim 12 , wherein the compound represented by formula (7) is methyl bromodifluoroacetate or ethyl bromodifluoroacetate. 
     
     
       14. The method according to any one of  claims 1  to  5  and  6 , wherein a reaction solvent in the step (E) is dimethyl sulfoxide or a mixed solvent of dimethyl sulfoxide and tetrahydrofuran. 
     
     
       15. The method according to any one of  claims 1  to  5 , comprising, in the case where R 2  of the compound represented by formula (8) is a group other than a methyl group, a step of transesterifying the R 2  into a methyl group before the step (F). 
     
     
       16. A compound of the following (a) to (g):
 (a) 1-(2-iodo-6-methylbenzyl)-3-methyl-6-nitro-1H-indazole; 
 (b) 3-methyl-2-[(3-methyl-6-nitro-1H-indazol-1-yl)methyl]benzonitrile; 
 (c) 2-[(6-amino-3-methyl-1H-indazol-1-yl)methyl]-3-methylbenzonitrile; 
 (d) 2-[(6-amino-3-methyl-1H-indazol-1-yl)methyl]-3-methylbenzonitrile hydrochloride; 
 (e) 2-[(6-iodo-3-methyl-1H-indazol-1-yl)methyl]-3-methylbenzonitrile; 
 (f) Methyl [1-(2-cyano-6-methylbenzyl)-3-methyl-1H-indazol-6-yl]difluoroacetate; or 
 (g) Ethyl [1-(2-cyano-6-methylbenzyl)-3-methyl-1H-indazol-6-yl]difluoroacetate.